Systematic review of autosomal recessive ataxias and proposal for a classification

Abstract

BackgroundThe classification of autosomal recessive ataxias represents a significant challenge because of high genetic heterogeneity and complex phenotypes. We conducted a comprehensive systematic review of the literature to examine all recessive ataxias in order to propose a new classification and properly circumscribe this field as new technologies are emerging for comprehensive targeted gene testing.MethodsWe searched Pubmed and Embase to identify original articles on recessive forms of ataxia in humans for which a causative gene had been identified. Reference lists and public databases, including OMIM and GeneReviews, were also reviewed. We evaluated the clinical descriptions to determine if ataxia was a core feature of the phenotype and assessed the available evidence on the genotype-phenotype association. Included disorders were classified as primary recessive ataxias, as other complex movement or multisystem disorders with prominent ataxia, or as disorders that may occasionally present with ataxia.ResultsAfter removal of duplicates, 2354 references were reviewed and assessed for inclusion. A total of 130 articles were completely reviewed and included in this qualitative analysis. The proposed new list of autosomal recessive ataxias includes 45 gene-defined disorders for which ataxia is a core presenting feature. We propose a clinical algorithm based on the associated symptoms.ConclusionWe present a new classification for autosomal recessive ataxias that brings awareness to their complex phenotypes while providing a unified categorization of this group of disorders. This review should assist in the development of a consensus nomenclature useful in both clinical and research applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s40673-017-0061-y) contains supplementary material, which is available to authorized users.

Extending the Phenotypic Spectrum Associated with STUB1 Mutations: A Case of Dystonia

“…When investigating a condition encompassing ataxia and dystonia it is important to consider accompanying features and family history. When family history is suggestive of an autosomal‐recessive pattern of inheritance, Friederich's ataxia (ATX‐FXN), ataxia‐telangiectasia (ATX‐ARL13B, ATX‐ATM), and AOA1 (ATX‐APTX) and 2 (ATX‐SETX) are the top differential diagnoses . It is prudent to remember the reversible causes of ataxia such as vitamin E deficiency (ATX‐TTPA; clues include proprioception loss, pyramidal signs, retinopathy), Refsum's disease (ATX‐PHY; anosmia, retinitis pigmentosa, hearing loss, ichthyosis), or biotin‐thiamine‐responsive basal ganglia disease (mutations in the SLC19A3 gene) .…”

“…Genetic analysis for spinocerebellar ataxia (SCA) 1, 2, 3, and 6 and dentatorubral–pallidoluysian atrophy was negative. We tested for the common causes of autosomal recessive (AR) ataxia such as spastic paraplegia type 7 (HSP/ATX‐SPG7), and Friederich's ataxia (ATX‐FXN) that were all negative . Testing for pathogenic variants in the proteolipid protein 1 gene (Pelizaeus Merzbacher syndrome; HSP/ATX‐PLP1) was normal.…”

“…Subacute‐onset cerebellar ataxia affecting siblings and skipping generations is suggestive of an autosomal‐recessive hereditary ataxia, including Friedreich's ataxia (ATX‐FXN), ataxia‐teleangiectasia (ATX‐ARL13B, ATX‐ATM), ataxia with oculomotor apraxia (AOA1 and AOA2; ATX‐APTX and ATX‐SETX), and autosomal‐recessive spinocerebellar ataxia (SCAR), especially after nongenetic causes of cerebellar degeneration have been ruled out …”

Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy

“…Common forms of recessive ataxias include ataxia-telangiectasia, Friedreich ataxia and ataxia oculomotor apraxia. Wide phenotypic variability is observed even with mutations in the same ARCA-related gene 3. Uncommon ARCA forms constitute a heterogeneous group of disorders with early onset ataxia as the predominant feature; intellectual disability is present in >60% of these patients 1.…”

“…Uncommon ARCA forms constitute a heterogeneous group of disorders with early onset ataxia as the predominant feature; intellectual disability is present in >60% of these patients 1. Mutations in >45 genes are known to cause ARCA, yet the molecular causes of ARCA in many patients remain unknown 3. Recently, homozygosity for PITRM1 R183Q was described in a Norwegian brother and sister in their late 60s with recessive spinocerebellar ataxia 4.…”